Combined monitoring of evoked potentials during microsurgery for lesions adjacent to the brainstem and intracranial aneurysms

Neurophysiologic monitoring during surgery is to prevent permanent neurological injury resulting from surgical manipulation. To monitor the integrity of nervous function during a surgical procedure with a risk of injury to the structures of the nervous system, either somatosensory evoked potentials (SSEPs) or brainstem auditory evoked potentials (BAEPs) have been applied for lesions adjacent to the brainstem as well as intracranial aneurysms. SSEPs are an established modality for monitoring of the function of the somatosensory pathways during surgery on the spinal cord and cerebrum, but this method is not reliable for monitoring motor function.^1,2 Moreover, BAEPs reflect functional state of the brainstem indirectly by evaluation of the brainstem auditory sensory pathways. These methods could not present a complete, accurate status of the motor pathway system. The compound muscle action potentials (CMAPs) evoked by transcranial electrical stimulation (TES) to the motor cortex, i.e. myogenic motor evoked potentials (myogenic MEPs), are regarded as pure motor evoked potentials³ for intraoperative monitoring of motor function. To improve the accuracy and sensitivity of intraoperative neuro-monitoring, we applied EPs monitoring to microsurgical procedures for lesions adjacent to the brainstem and intracranial aneurysms in 68 consecutive patients from March 2006 to July 2007. This clinical prospective study was undertaken to investigate the feasibility, safety, and sensitivity of the combined use of EPs for monitoring motor function and the impact on surgery. Although the protection of function of the cranial nerves is extremely important for microsurgery for lesions adjacent to the brainstem, it is not discussed in this study.

Patients
Operations were performed on 68 consecutive patients (27 men, 41 women) with lesions adjacent to the brainstem as well as intracranial aneurysms. Their age ranged from 15 to 66 years (average 43.5 years). Before operation, the patients were subjected to computed tomography (CT), computed tomography angiography (CTA), magnetic resonance imaging (MRI), or digital subtraction angiography (DSA). Of these patients, 29 had lesions adjacent to the brainstem, showing that the brainstem was compressed to different extent by vestibular neurinomas (19 patients), trigeminal neurinomas (2), meningeomas of the foramen magnum (4), neurinoma of the jugular foramen (1), ependymoma of the fourth ventricle (1), neurinoma of the petrous apex (1) and odontoid bone deformity(1). The other 39 patients had intracranial aneurysms of the anterior circulation (36 patients) and posterior circulation (3). Preoperatively, myodynamia was above level 3 in all patients, with level 5 in 49 patients and level 3 to 4 in 19. The patients with severe motor dysfunction (myodynamia below level 2) were excluded preoperatively. No history of implantation of cardiac pacemaker, epileptic seizure, cranial defect, hydrocephalus, and heart diseases was found in the patients.

Anesthesia management and muscle relaxant
Anesthesia was induced by bolus injection of propofol 100 mg, fentanyl 0.1 mg and vecuronium 50 mg. Two methods were adopted for the maintenance of the anesthesia. One was intravenous-inhalation combined anesthesia for operations on 27 patients, with continuous infusion of propofol 2 to 6 mg·kg^-1 body weight·h^-1, fentanyl 0.1 mg/h, and inhalation of N₂O (nitrous oxide) or isoflurane at a low concentration (< 0.5 minimal alveolar concentration, MAC). The controlled hypotension was adopted intraoperatively in 4 of the 27 patients at the concentration of inhaled isoflurane up to 1.5 to 1.8 MAC. The other was total intravenous anesthesia (TIVA) and it was given to 41 patients with continuous infusion of 6 to 10 mg·kg^-1 body weight·h^-1 isoflurane and 50 µg/h fentanyl. In all patients, continuous infusion of 2 to 3 mg/h vecuronium was performed during surgery, and train of four twitch test (TOF) was used to monitor the blockage degree of neuro-muscle.

Blood pressure, blood-oxygen concentration, carbon dioxide concentration, pulse and temperature were monitored intraoperatively. If necessary, air temperature of operating room should be increased to prevent the low temperature of the patients.

Monitoring of evoked potentials
Monitoring of TES-MEPs and SSEPs was attempted intraoperatively in the 68 patients, of whom 28 patients with tumors of the posterior cranial fossa (except for 1 odontoid bone deformity because of instrument failure) and 3 patients with aneurysms of the posterior circulation were also subjected to monitoring of BAEPs. Epoch XP Neurological Workstation (Axon system, USA) was used to monitor the changes of evoked potentials intraoperatively. When the changes were approaching the warning criteria, interventional measures should be taken accordingly.

Monitoring of TES-MEPs
Multi-pulse TES was performed using the D185 stimulator (Digitimer, Welwyn, Garden City, UK).The corkscrew electrodes were used as stimulating electrodes, and the subdermal needle electrodes as recording electrodes. According to the international 10 to 20 system instituted by the International Electroencephalographic Society, the stimulating electrodes were placed 1 to 2 cm anterior to C3/C4 or C1/C2, and the cathode was set at the opposite site. Short train transcranial electrical stimulation was initiated with 5 to 7 square-waves from the anode at a duration of 300 μs, an interstimulus interval of 2 ms (500 Hz repetition frequency), and a maximum stimulation voltage of 700 V. Meanwhile, myogenic MEPs from the bilateral biceps brachii, abductor pollicis brevis, anterior tibial muscle and abductor hallucis were recorded. At least, myogenic MEPs should be elicited from one of the targeted muscles. The value of MEPs 40 minutes after anesthesia was regarded as the baseline, the warning criterion after intravenous-inhalation combined anesthesia as the disappearance of myogenic MEPs, and the warning criterion after TIVA as the amplitude reduction of MEPs over 80% compared with the baseline.⁴

Monitoring of SSEPs
Subdermal needle electrodes were used as recording and stimulating electrodes. To record SSEPs from the upper limbs, the reference electrodes were placed at the Fz point and the recording electrodes were set at the C3', C4' and bilateral Erb's points respectively. The stimulating electrodes were placed on the bilateral median nerves at both wrists, with an stimulating intensity ranging from 15 to 25 mA, a frequency of 3.1 Hz, a wave band ranging from 50 to 300 Hz, and an analysis time for 50 ms. To record SSEPs from the lower limbs, the recording electrodes were placed at the Cz point and the bilateral popliteal fossa respectively. The stimulating electrodes were placed on the bilateral posterior tibial nerve at the medial malleolus, with a stimulating intensity ranging from 20 to 30 mA, an analysis time for 100 ms, and the other parameters as same as those of SSEPs monitoring in the upper limbs. The signals were averaged 200 times. During the operation, the cortex potentials of the operated side included N20-P25 compound wave for the upper limbs and P37-N45 compound wave for the lower limbs. Potentials of the opposite cortex and peripheral potentials were used for the exclusion of the influence of anesthesia and other interfering factors. The value of SSEPs 40 minutes after anesthesia was regarded as the baseline and the warning criterion as the amplitude reduction over 50% in contrast to the baseline or as the prolonged latency for more than 10%.⁵

Monitoring of BAEPs
Subdermal needles used as the recording electrodes were placed at the processes of the bilateral mastoids. The reference electrodes were placed on the Cz point. When auditory clicking sound stimulation (disperse-dense waves) was utilized with a frequency of 11.1 Hz at 100dBnHL, the opposite ear canal was masked by 100dBnHL white noise. Wave band was set from 30 to 1500 Hz, with the stimulating time for 15 ms. One thousand responses were averaged. The principal intraoperative parameters included amplitude and response latency of V-wave. The warning criteria included prolonged latency of V-wave more than 0.8 ms or reduction of amplitude for more than 50% of the baseline.⁵

Train of four twitch test (TOF)
Four consecutive electrical stimuli of 2 Hz (interval 0.5 s) were given to the left median nerve, while the recording electrodes were placed at the left abductor pollicis brevis.

Assessment of postoperative motor function
The neurological state of patients was evaluated on the day before operation, the day of operation, the first day, the third day, and the first week after operation. Within 24 hours after operation, myodynamia which decreased to ≥ level 1 compared with that before operation was defined as a new motor dysfunction in one limb or more limbs.

Data analysis
During the operation, the data of electrophysiological monitoring and important events were both recorded. The correlation of monitoring results and clinical outcome was studied prospectively.

Feasibility and safety of combined monitoring of EPs
Monitoring of MEPs was impossible in 4 (5.9%) of the 68 patients (intraoperative controlled hypotension, isoflurane concentration was up to 1.5 to 1.8 MAC). Combined intraoperative monitoring of EPs was successful in the other 64 operations (94.1%). No complication resulting from EPs monitoring was found in all patients.

Intraoperative monitoring of EPs and postoperative motor function (Fig. 1)
Combined monitoring of TES-MEPs and SSEPs was attempted in 37 of the 68 patients. In 3 patients with critical changes of MEPs and SSEPs, one had motor dysfunction postoperatively. In 4 patients with critical changes of MEPs only, 2 patients had postoperative motor impairment. In 4 patients without MEPs elicited, SSEPs were stable and no motor dysfunction happened. In the other 26 patients with stable EPs, no motor dysfunction appeared on the 1st day postoperatively, but there was temporary muscle weakness in 2 patients with intracranial aneurysm on the 2nd and 5th postoperative day respectively.

Combined monitoring of TES-MEPs, SSEPs and BAEPs was attempted in the other 31 patients. In 5 patients with critical changes of MEPs, SSEPs and BAEPs, 4 patients had motor dysfunction postoperatively. In 2 patients with critical changes of MEPs only, 1 patient had postoperative motor impairment. These 5 patients with postoperative motor impairment (myodynamia decreased to levels 1 to 3) had large tumors, including 2 vestibular neurinomas, 1 trigeminal neurinoma, 1 meningeoma of the foramen magnum and 1 ependymoma of the fourth ventricle. In the other 24 patients, including 21 patients with stable EPs, 2 patients with critical changes of SSEPs and 1 patient with critical changes of BAEPs, no motor dysfunction occurred.

Specificity and sensitivity of motor function monitoring
Despite instrument weakness and anesthetic effect, 8 of 14 patients with critical changes of MEPs demonstrated postoperatively new motor impairment, including 5 patients with temporary new paresis and 3 patients with permanent new paresis. Furthermore, there were 5 patients with critical changes of SSEPs and 4 patients with critical changes of BAEPs in the above-mentioned 8 patients. The correlation between intraoperative changes of MEPs and postoperative motor function was observed (Table 1).

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Table 1. Correlation of motor evoked potential findings and motor outcome in 64 cases

Intraoperative changes of MEPs (Table 2)
According to the changes of MEPs, 13 patients received intraoperative intervention. Among them, 6 patients with complete or incomplete recovery of MEPs showed no motor dysfunction (Figs. 2, 3), 4 patients with incomplete recovery and 1 patient with no recovery of MEPs had temporary motor dysfunction, and 2 patients without recovery of MEPs had permanent paresis（Fig. 4）. In one patient with an anterior communicating aneurysm, MEPs and SSEPs from the limbs opposite to the side of operation were not elicited at the beginning of the operation. This was misdiagnosed to be due to failure of instrument and abscence of corresponding intervention. Motor dysfunction and disturbance of consciousness occurred postoperatively.

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Table 2. MEPs changes and correlation between monitoring results and clinical outcome

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Fig. 2. A right PCoA aneurysm. The aneurysm ruptured at the time of dissection and temporary clipping. A: preoperative DSA showing a right PCoA aneurysm (red arrow); B: postoperative CTA scan showing the aneurysm clipped (red arrow); C, D: tracings showing the results of intraoperative monitoring of MEPs and SSEPs. MEPs recorded from the left abductor pollicis brevis (L APB) and SSEPs from Fpz-C4′ montage lost intraoperatively after artery clipping (red arrow) and completely recovered (black arrow) after removal of the clip. The patient did not develop postoperative nerve impairment.

Feasibility and safety of combined monitoring of EPs
With the introduction of the multiple-pulse stimulation technique^6,7 and TIVA protocol, it is possible to record MEPs from distal muscles of the limbs by transcranial electric stimulation on the motor cortex intraoperatively. The success rate is mainly dependent on the anesthetic protocol adopted and patients' state of motor function before operation.^2,8-10 In our study, the success rate was as high as 94.1%, confirming that it could be used intraoperatively. In a report,¹¹ MEPs could not be elicited in 4 cases owing to the inhaled concentration of isoflurane for 1.5 to 1.8 MAC. In our practice, continuous infusion of propofol and fentanyl-with no boluses, avoiding halogenated agents and high dose of muscle relaxants after intubation, has been feasible for most procedures.

Despite such complications as bite injury, movement-induced injury, seizure of epilepsy, arrhythmia and scalp burn which may be caused by TES to the motor cortex, the reported incidence rate is very low.^4,12 No such complications happened in our series. Thus TES-MEPs are applicable in intraoperative monitoring of motor function. Furthermore, the relative contraindications of TES-MEPs monitoring should be emphasized especially for those patients with cardiac pacemaker.

Sensitivity of monitoring of EPs to motor function
In our series, 8 patients sustained new motor dysfunction detected by MEPs (8 patients), SSEPs (5) or BAEPs (4) respectively, suggesting a close correlation between the postoperative motor function and the results of TES-MEPs monitoring. TES-MEPs is superior to SSEPs and BAEPs in the detection of motor dysfunction; it is safe, effective and invasive for intraoperative monitoring the function of the nervous system.

Warning criteria of TES-MEPs monitoring
No accepted warning criteria are available for TES-MEPs monitoring at present. Because of its instability and high sensitivity, a decrease of intraoperative myogenic MEPs for more than 80% of the baseline is regarded as the warning criterion,⁵ or “yes or no” of the potential signal as an indicator of damage. The disappearance of the myogenic MEPs is not an excessively late sign of ischemia, compression or traction.⁴ Meanwhile a decrease of myogenic MEPs for more than 50% of the baseline is regarded as the warning criterion by others, giving a higher false positive rate.¹⁰ For “yes or no” as a warning criterion in this study, a close correlation was observed between intraoperative monitoring of MEPs and postoperative motor function. In 41 operations using TIVA, the waveform of MEPs was much stable. If MEPs were stable, a decrease of intraoperative MEPs for more than 80% of the baseline could be used as a warning criterion; if not, “yes or no” as a warning criterion could be used.

Impact on surgical strategy
Intraoperative conditions or events can cause cerebral infarction in the major cerebral arteries supplying the cortex and superficial subcortical structures or in the perforating arteries feeding the deep subcortical structures and postoperatively impaired neurological function including intentional and inadvertent occlusion of vessels, compromise to the small perforating vessels during dissection, and disturb local microcirculation by retraction of brain tissue. Monitoring of SSEPs and BAEPs is usually utilized in surgical treatment of patients with intracranial aneurysms. However, impairment of the nervous system（incomplete paralysis）was observed in a lot of cases that did not show abnormal SSEPs intraoperatively,¹³ possibly because of internal capsule or brainstem ischemia.¹⁴ Hence monitoring of SSEPs may be less efficient in predicting ischemia in the cortical and subcortical area (excluding the somatosensory cortex and sensory pathway). Microvascular Doppler ultrasono- graphy (MDU) can detect inadvertent vessel occlusion directly after clip placement but the conditions of remote collateral flow and the flow of important small perforating vessels.¹⁴ In our series, after interventional measures were taken for 6 patients with critical changes of MEPs during the operation for intracranial aneurysm, complete or partial recovery was achieved in 5 patients, of whom 2 developed temporary muscle weakness. In one patient, MEPs and SSEPs from the limbs opposite to the operative side could not be elicited. This was misdiagnosed to be caused by failure of monitoring instrument and absence of corresponding intervention.

Postoperative motor dysfunction and disturbance of consciousness occurred. Therefore, combined monitoring of EPs is sensitive to detect insufficiency of the remote collateral flow, and intraoperative changes of EPs demonstrate the changes of blood-supply to the corresponding areas. Thus operative techniques (including recovery of blood supply, modification of permanent or temporary vessel clips, decreased excessive traction of brain tissue or application of papaverine for relief of vessel spasm) could be modified to prevent the occurrence of postoperative ischemic complications.

The use of temporary clips is related to a high risk of intraoperative stroke, especially in cases complicated with intraoperative rupture of aneurysm.¹⁵ Temporary artery clipping was used in 22 (56.4%) patients of our series, with a duration ranging from 3 to 10 minutes in 18 patients. The waveform was not significantly changed and also sensory or motor function was not impaired postoperatively. We suggest artery clipping in surgery for intracranial aneurysm be less than 10 minutes.¹⁶ However, there is individual difference in the tolerance to ischemia. In our series, one patient with operative rupture of aneurysm at the left giant middle cerebral artery was subjected to artery clipping for 20 minutes. However intraoperative changes of MEPs and SSEPs did not reach the warning criteria and operation was continued for complete occlusion of aneurysm. Whereas one patient with an aneurysm of the right posterior communicating artery showed a remarkable reduction of MEPs at 6 minutes after the artery clipping. Then the MEPs were totally vanished and the SSEPs decreased at 11 minutes. By removing the clip and soaking the vessel with narceine solution, the waveform of EPs fully recovered. In another patient with aneurysm of the middle cerebral artery, MEPs disappeared without recovery when lateral fissure was dissected, and SSEPs disappeared at 3 minutes after temporary artery clipping and completely recovered after removal of the clip. We considered that intraoperative collection of intracranial air led to increasing resistance of TES.¹⁰ These 3 patients did not have postoperative nerve impairment. In short, combined intraoperative monitoring of EPs provides real-time information of pathological changes. It is helpful to determine subsequent operation and avoid excessive cerebral damage.

Intraoperative monitoring of EPs during surgery for lesions adjacent to the brainstem aims to protect the function of the brainstem and cranial nerves. Traditional intraoperative neurophysiological methods (e.g., SSEPs and BAEPs) are capable of evaluating only 20% of the brainstem. The data cannot be obtained in real time with these methods, with a delay of one minute or so. MEPs have recently been used for monitoring the function of the corticospinal tract, cortico-bulbar tract and cranial nerve during surgery on tumor of the posterior cranial fossa and brainstem,^4,17-20 whereas combined SSEPs and BAEPs reduce the rate of false negativity and positivity.²¹ Because of compression or retraction of the brainstem by intraoperative tumor resection or hemostasis, 5 of our patients had critical changes of MEPs. After the improvement of surgical manipulation, 2 patients with complete or incomplete recovery of MEPs showed no motor dysfunction. Three patients with incomplete or no recovery demonstrated temporary motor dysfunction. MEPs disappeared in 2 patients with a large vestibular neurinoma and without recovery and permanent paresis happened postoperatively. Obviously, MEPs are superior to SSEPs and BAEPs in detecting impending impairment of the functional integrity of the brain during surgery. Detection of MEPs changes and adjustment of surgical strategy can prevent irreversible damage to the pyramidal tract.

Advantage of monitoring of MEPs and SSEPs
SSEPs may be more reliable than MEPs in predicting cortical blood supply because TES could partially excite the subcortical corticospinal tract. Both of SSEPs and MEPs reflect the functional state of different nervous pathways. SSEPs monitoring is less affected by different anesthetics or neuromuscular blocking agents, and giving a little bit of interference to the operation. MEPs are used for real-time intraoperative monitoring without signal averaging. Hence combined MEPs and SSEPs could make monitoring of the integrity of nervous function more completely and accurately.

Influence of EPs on the morbidity
Intraoperative monitoring of EPs could detect the potential risk of operative procedures and improve the safety of subsequent procedures. But its effectiveness in decreasing the overall morbidity awaits further investigation because of some irreversible intraoperative injuries and unpredictable postoperative injuries of nervous function. In two operations on aneurysms in our study, no motor dysfunction was found on the day of operation but temporary hemiplegia on the 2nd and 5th postoperative day, which was relevant to vascular spasm. In the other two patients with large vestibular neurinomas, though interventional measures were taken, MEPs disappeared because of compression of the brainstem by intraoperative hemostasis and occurrence of permanent postoperative paresis.

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